This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Erb family of receptors activates a multi-layered network mediating crucial pathways leading to cell proliferation, differentiation, migration, and metabolism, in response to many related activating growth factors. Thus, a quantitative description of the receptor activation from a molecular perspective, as well as the signal transduction resulting form protein-protein interactions in networks, are both essential to pin-down the origin of inhibitor sensitivity and drug resistance. The process of ligand-induced dimerization and activation of the extracellular domain is now well understood. Precisely how this ligand-induced dimerization event is coupled to, and leads to, activation of the intracellular tyrosine kinase domain is only now emerging from recent studies. In our laboratory, we propose to carry out multiscale simulations to help identify the role, cause, and significance of drug sensitizing mutations of the Erb family RTKs. We seek to computationally study the modes of activation of Erb RTKs, and how the mutation landscape alters the activation mechanism. Our results will thus serve to identify constitutively active mutants, and will help formulate a paradigm to understand the Erb family RTK dependence (and sensitivity) to small molecule inhibitors. The outcome of our studies will significantly impact the optimization of small molecule therapeutic inhibition strategies. The overarching goal is to delineate the free energy landscape and structurally characterize the molecular pathway that describes the transition between the inactive and active conformations in a fully atomistic, explicitly solvated wildtype ErbB1 (EGFR) receptor tyrosine kinase (RTK) dimer system and to study the pathway for the subsequent ErbB1 catalyzed phosphorylation of substrate tyrosines. Our proposed efforts are categorized into four projects: Project (a) Classical MD, Project (b) Umbrella Sampling, Project (c) Transition Path Sampling, and Project (d) QMMM Simulations. The simulation results will be validated through a collaboration with Mark Lemmon's lab at Penn by computationally identifying new mutations that are crucial to the delineated molecular pathway and verifying their role in the cellular experiments.